NEW ASPECTS OF DNA RECOGNITION BY NUCLEAR RECEPTORS

核受体 DNA 识别的新方面

• 批准号: 2623459
• 负责人: Martin L. Privalsky
• 金额: $ 16.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-23 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2623459
• 关键词: DNA binding protein; RNA splicing; chromosome translocation; dimer; genetic regulatory element; high performance liquid chromatography; hormone receptor; nuclear membrane; nucleic acid sequence; phosphorylation; polymerase chain reaction; posttranslational modifications; protein sequence; protein structure; receptor binding; tissue /cell culture; transcription factor

Our ultimate goal is to better understand how different nuclear hormone receptors recognize different target DNA sequences. Nuclear hormone receptors are ligand-regulated transcription factors, and modulate the expression of specific target genes in response to small hydrophobic hormones, such as steroids, thyroid hormones, and retinoids. The DNA recognition properties of each receptor play the critical role of defining the particular repertoire of target genes which respond to a given hormone. However, our understanding in incomplete of how the nuclear receptors, which posses generally similar zinc-finger domains, manifest the specificity necessary to recognize inherently distinct sets of target genes. Recent work by ourselves and others has revealed that: (A) regions outside of the zinc-finger domain play critical and unanticipated roles in DNA sequence-specificity, (B) nuclear hormone receptors recognize DNA binding sites not only as protein dimers, but also by novel mechanisms involving monomers and high-order oligomeric complexes, and ~ post-translational protein modifications can alter DNA recognition. These observations confirm that important elements of DNA recognition by nuclear receptors have not been previously explored, and suggest plausible mechanisms by which the specificity of different receptors for different target genes is generated and defined. We will investigate: A. How do different nuclear receptors recognize distinct DNA half- sites? B. What are the different roles of protein monomers, dimers and oligomers in DNA recognition by different members of the nuclear hormone receptor family. C. Is the mode and specificity of DNA recognition by nuclear receptors altered by post-translational modification, alternative splicing, or chromosomal translocations? Nuclear hormone receptors play central roles in metazoan homeostasis, development, and differentiation. Aberrant human receptors have been implicated in many endocrine and neoplastic diseases. Our experiments will help resolve important aspects of nuclear hormone receptor signaling and physiology, and will also contribute toward a broader comprehension of how DNA recognition specificity is achieved by other transcription factors.

我们的最终目标是更好地了解核如何不同 激素受体识别不同的靶DNA序列。 核 激素受体是配体调节的转录因子，并且 调节特定靶基因对小的表达 疏水激素，例如类固醇，甲状腺激素和 视网膜类似。 每个受体的DNA识别特性 定义靶基因的特定曲目的关键作用 对给定激素的反应。 但是，我们的理解 核受体如何不完整 相似的锌指域，表明了 识别固有不同的靶基因集。 最近的工作 我们自己和他人透露：（a） 锌指域在DNA中扮演关键和意外的角色 序列特异性，（b）核激素受体识别DNA 绑定位点不仅是蛋白质二聚体，而且是新颖的 涉及单体和高阶寡聚复合物的机制， 〜翻译后蛋白质修饰可以改变DNA 认出。 这些观察结果证实了 核受体识别的DNA识别以前尚未 探索并提出了合理的机制 生成了不同靶基因的不同受体的 定义。 我们将调查： 答：不同的核受体如何识别独特的DNA半 - 网站？ B.蛋白质单体，二聚体和 核的不同成员识别DNA的低聚物 激素受体家族。 C.是核DNA识别的模式和特异性 受体通过翻译后修饰改变，替代性 剪接还是染色体易位？ 核激素受体在后生动体稳态中扮演着核心角色， 发展和差异化。 异常的人类受体已经 与许多内分泌和肿瘤疾病有关。 我们的 实验将有助于解决核激素的重要方面 受体信号传导和生理，也将有助于 更广泛地理解如何实现DNA识别特异性 由其他转录因子。